Non-steroidal anti-inflammatory drugs (NSAIDs) are used extensively for the treatment of inflammatory conditions, including pain-releasing, anti-pyretic and rheumatoid arthritis. These functions are believed to inhibit the enzyme cyclooxygenase (COX) that is involved in the biosynthesis of prostaglandins G and H from arachidonic acid. So far two isozymes of COX are known: COX-1 and COX-2. COX-1 is constitutively produced in a variety of tissues and appears to be important to the maintenance of normal physiological functions, including gastric and renal cytoprotection. The COX-2 is an inducible isozyme, which is produced in cells under the stimulation of endotoxins, cytokines, and hormones and catalyzes the production of prostaglandins which cause inflammation.
The currently therapeutic use of NSAIDs has been associated with the inhibition of both COX-1 and COX-2 and causes well-known side effects at the gastrointestinal and renal level. Therefore, the selective COX-2 inhibitors could provide anti-inflammatory agents devoid of the undesirable effects associated with classical, nonselective NSAIDs. In addition, COX-2 is over-expressed in colon cancer tissue. COX-2 inhibitors possess potential prophylactic and therapeutic application to colon cancer.
The COX-2 inhibitors as selective anti-inflammatory drugs are chemically aminosulfonylaryl or methylsulfonylaryl-containing substances, such as Nimesulide (R. H. Brogen and A. Ward. Drugs, 1998, 36: 732–753), NS-398 (JP 292856, JP 871119), Meloxicom(DE 2756113, DE 771216), pyrrazole-containing tricyclic compounds, for example, Celecoxib(WO 9641825, WO 961227), oxazole-containing tricyclic compounds, for example, JRE-522(EP 745598, EP 961204), unsaturated gamma-lactone-containing compounds, for example, Rofecoxib (EP 788476, WO 9613483). The non-selective NSAID Indomethacin as a lead compound was chemically modified to give rise to selective COX-2 inhibitors without sulfonyl groups, for example L-748780 and L-761066 (W. C. Black et al. Bioorg Med. Chem. Lett. 1996, 6: 725–742, WO 9730030). These compounds exhibit a selective COX-2 inhibition to different extents, and constitute a group of anti-inflammatory drugs with little adverse reactions. Reports on the sulfonyl-containing 3,4-diphenyl-2,5-dihydropyrrolyl-2-ones and their inhibitory properties for COX-2 has not been found so far in the pharmacological literature.